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MOTS-c

Also known as Mitochondrial ORF of the 12S rRNA type-c, MOTSc

Mitochondrially encoded peptide that regulates metabolism via AMPK; studied almost entirely preclinically.

preclinical Metabolic & weight research chemical

At a glance

Category
Metabolic & weight
Status
research chemical
Route
subcutaneous or intraperitoneal in animal studies; subcutaneous in user protocols
Half-life
short; in animal studies on the order of tens of minutes to a few hours. Not reliably determined in humans
Onset
not established in humans
Molecular weight
approximately 2174 g/mol
Sequence
MRWQEMGYIFYPRKLR

Not approved for human use in the EU or US. There are no registered medicines containing MOTS-c. Sold online as a 'research chemical'.

Doping status: Not explicitly named on the WADA list; as a non-approved substance it in all likelihood falls under S0

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame within the mitochondrial 12S rRNA gene. It therefore belongs to the mitochondrially encoded peptides (MDPs), along with humanin and the SHLP family. It is thus not a classical hormone from an endocrine gland, but a signalling molecule that acts from the mitochondrion on the rest of the cell and on other tissues.

The described mechanism of action runs via the folate-purine-AMPK pathway. MOTS-c inhibits the folate cycle, which reduces de novo purine synthesis and causes AICAR to accumulate; AICAR then activates AMP-activated protein kinase (AMPK) 1. AMPK activation shifts cell metabolism towards catabolism: more glucose uptake via GLUT4 translocation, more fatty acid oxidation, less lipogenesis.

Under metabolic stress MOTS-c translocates to the cell nucleus, where together with transcription factors of the ATF/CREB family it influences the expression of antioxidant and metabolic genes. This makes MOTS-c one of the few described examples of direct retrograde signalling from the mitochondrial genome to the nuclear genome.

In humans MOTS-c is found at raised levels in muscle tissue and plasma after exercise, which has earned it the label 'exercise mimetic'. That term describes an overlapping signalling pathway, not a demonstrated replacement for physical training.

What the research shows

The evidence is almost entirely preclinical. The biology of MOTS-c as an endogenous peptide is well documented — its identification, the AMPK pathway and the exercise-related rise have been described in peer-reviewed journals. What is missing is evidence that exogenous administration has a clinically relevant effect in humans.

Research in humans

There are no published randomised clinical studies of MOTS-c administration to humans. The human research is observational: plasma and muscle concentrations of endogenous MOTS-c rise after exercise, fall with age and are lower in insulin resistance. A polymorphism in the MOTS-c coding region (m.1382A>C) has been associated in Japanese cohorts with reduced risk of type 2 diabetes in men. These are correlations in endogenous levels, not evidence that injecting it works.

Animal and lab research

Lee et al. (Cell Metabolism, 2015) showed in mice that administration of MOTS-c counteracts insulin resistance caused by a high-fat diet and inhibits weight gain 1. Reynolds et al. (Nature Communications, 2021) described that MOTS-c administration in old mice improved physical performance capacity and muscle homeostasis 2. These studies generally used daily intraperitoneal injections at doses that cannot be scaled directly to humans.

Caveats. No human interventional studies, so no data on efficacy, dosing or safety when administered to humans. The half-life is short, which raises the question of how intermittent injections would produce a lasting effect. Animal models often used young, healthy or specifically diseased animals, which limits translatability. Detection and quantification of MOTS-c in plasma is methodologically contested, which makes some observational findings hard to replicate.

What it is used for

  • Studied in animal models of insulin resistance, obesity and metabolic syndrome, where administration counteracted diet-induced insulin resistance and inhibited weight gain in mice 1
  • Studied in animal models of age-related decline in muscle function, where administration improved physical capacity and muscle homeostasis in old mice 2
  • Used outside a study setting for supposed effects on fat loss, energy and 'longevity'; none of these applications has been studied in humans
  • Used in laboratory research as a tool to study AMPK signalling, the pathway through which MOTS-c was shown to act via inhibition of the folate cycle and accumulation of AICAR 1

Dosing

Dose
In online user protocols usually 5-10 mg per week, spread over several injections
Frequency
In user protocols 2-3x per week; in animal studies often daily
Route
Subcutaneous
Duration
In user protocols 4-10 weeks; not based on study data
  • There is no clinically validated dosing schedule for humans. All doses mentioned come from online user protocols and not from controlled research.
  • The doses in animal studies (expressed in mg/kg intraperitoneally) cannot simply be converted into a safe or effective human dose 12.
  • Because there are no human efficacy data, any recommended dose is essentially speculative.
  • The short half-life makes it unlikely that twice- or three-times-weekly injections produce the continuous AMPK activation seen in the animal studies with daily administration.
  • The schedule in the section below is what circulates among users; it has no published pharmacokinetic or safety basis. Unusually for this class, MOTS-c is genuinely dosed in milligrams, not micrograms, so someone applying microgram-scale habits from GH peptides would under-dose by a thousandfold. That is a real point of confusion in the reports.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Weekly subcutaneous course (user-reported)

user protocol — not validated

Source: Peptide and longevity forums and vendor pages

This is not a validated schedule. It is a pattern that circulates among users and sellers, reproduced because it is what people actually follow — not because it has been tested. No trial established these doses, this interval or this duration, and nobody is checking what is in the vial. Treat every number below as an assertion, not a finding.

Typical reported weekly total5-10 mg per week subcutaneously, split across several injections
Reported frequencytwo to three times per week; a minority run 'five days on, two off' at smaller daily amounts
Reported cycle lengthroughly 4 to 10 weeks, then a break of similar length

These amounts come from forum protocols and vendor labelling, not from any human study. Reported weekly totals spread widely, from about 5 mg to 30 mg, with no convergence, and the frequency sits awkwardly against the pharmacology: the animal work that generated interest used daily injections, while users inject two or three times a week, and MOTS-c's short half-life makes it doubtful that the intermittent schedule reproduces the sustained AMPK activation those studies relied on 1. Attribution is the deepest problem here. MOTS-c is described as an 'exercise mimetic' and almost everyone using it is also training and dieting, so any benefit is impossible to separate from the exercise itself. 'No effect' reports are common, and a plausible glucose-lowering action 1 means it is not risk-free for anyone on blood-glucose-lowering medication.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
5 mg, 10 mg
Solvent
bacteriostatic water (0.9% benzyl alcohol)
Storage
Reconstituted 2-8 °C, usually keeps for a few weeks. Lyophilised powder in the freezer, protected from light.

Worked example

10 mg vial + 2 ml bacteriostatic water = 5 mg/ml. The figures in the dosing section are weekly totals split over several injections, so a single injection of a 5 mg weekly total taken three times a week is about 1.7 mg, which is 0.33 ml, or 33 units on a U100 insulin syringe. Drawing the whole 5 mg weekly total in one go would be 1 ml, the entire barrel of a U100 syringe.

Do not shake; let the water run down the wall of the vial. The vial sizes and shelf lives given are common practice for unregistered peptides, not a manufacturer-validated specification. With unregistered product, identity, strength and sterility are not verified; the sequence contains two methionine residues and one tryptophan, all three of which are sensitive to oxidation, making degradation under improper storage plausible.

Work it out for MOTS-c

Safety

Side effects

  • No systematically collected side effect profile in humans — there are no clinical studies
  • Anecdotally reported: injection site reactions, fatigue, headache, temporary nausea
  • Theoretical risk: MOTS-c acts through AMPK activation and increased glucose uptake in mice 1, so a glucose-lowering effect is plausible and may matter when using blood-glucose-lowering medication. This has not been measured in humans
  • Theoretical consideration: AMPK plays a role in cell growth and autophagy; the effects of prolonged pharmacological activation have not been mapped
  • With unregistered product: risk of contaminants, endotoxins and infection with non-sterile preparation

Do not use if

  • Pregnancy and breastfeeding — no safety data
  • Hypersensitivity to the peptide or to benzyl alcohol in bacteriostatic water
  • Use of insulin or other blood-glucose-lowering medication without medical supervision, given the theoretical glucose-lowering effect
  • Active malignancy — the role of AMPK modulation in tumour growth is ambiguous and has not been studied in this context
  • Use on the assumption that efficacy in humans has been demonstrated — it has not

Interactions

Not systematically studied. On theoretical grounds, concurrent use with metformin may be relevant, since both act via AMPK; whether this is additive, synergistic or irrelevant has not been studied. The same applies to combination with insulin or sulfonylureas in connection with a possible glucose-lowering effect. There are no documented pharmacokinetic interactions.

Sources